It is estimated that in 1991, there will be 30,800 new cases of oral pharyngeal cancer and 8150 deaths from oral cancer in the United States. The vast majority of these cancers are related to tobacco use. N'- Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) are the only tobacco constituents known to induce oral cavity tumors in animals, and are believed to be important in the induction of human oral cavity cancers. It is our hypothesis that NNN and NNK are oral cavity carcinogens due to their tissue specific cytochrome P-450) mediated metabolism, and that individual susceptibility to tobacco related oral cancer, at least in part, depends on a person's ability to activate these tobacco specific nitrosamines (TSNA). The presence of unique P450s in the esophagus has been proposed to explain the striking sensitivity of this tissue to tumor induction by certain asymmetric nitrosamines. NNN and NNK are metabolized similarly by rat esophagus and oral cavity tissue. In this proposal we will characterize and compare the P450 mediated activation of nitrosamines in oral and esophageal tissue in the rat. The relative ease of obtaining human oral cavity tissue provides a unique opportunity to investigate carcinogen metabolism in people. Therefore, we will extend our studies on NNN and NNK metabolism in rat oral tissue to human oral tissue. We will determine which P450s are involved in the activation of NNN isozymes. In addition, we will determine the level of MRNA for specific classes of P450s in human and rat oral cavity tissue. The metabolism of NNN and NNK by human oral cavity microsomes will be compared to their metabolism by purified human liver P450s. The relationship of oral tissue metabolism in smokers to the levels of the HPB releasing adduct in hemoglobin from these same individuals will be determined. This TSNA derived adduct, described in Project 1, is present in Hb of tobacco users and suggested to be a measure of individual variability in TSNA metabolism.